Revaccination outcomes among adolescents and adults with suspected hypersensitivity reactions following COVID-19 vaccination: A Canadian immunization research network study.

BACKGROUND: COVID-19 vaccination has been associated with anaphylaxis and hypersensitivity reactions. Infectious disease physicians and allergists in the Canadian Special Immunization Clinic (SIC) Network developed guidance for evaluating patients with adverse events following immunization (AEFI) including suspected hypersensitivity. This study evaluated management and adverse event recurrence following subsequent COVID-19 vaccinations. METHODS: Individuals aged 12 years and older enrolled at participating SICs before February 28, 2023 who were referred for suspected or diagnosed hypersensitivity reaction following COVID-19 vaccination, or for prevaccination assessment of suspected allergy to a COVID-19 vaccine component were included. De-identified clinical assessments and revaccination data, captured in a centralized database, were analyzed. The Brighton Collaboration case definition (BCCD) for anaphylaxis (2023 version) was applied. RESULTS: The analysis included 206 participants from 13 sites: 26 participants referred for pre-vaccination assessment and 180 participants referred for adverse events following COVID-19 vaccination (15/180 [8.3%] with BCCD confirmed anaphylaxis, 84 [46.7%] with immediate hypersensitivity symptoms not meeting BCCD, 33 [18.3%] with other diagnosed hypersensitivity reactions, and 48 [26.7%] participants with a final diagnosis of non-hypersensitivity AEFI). Among participants referred for AEFIs following COVID-19 vaccination, 166/180 (92.2%) were recommended for COVID-19 revaccination after risk assessment, of whom 158/166 (95.2%) were revaccinated (all with a COVID-19 mRNA vaccine). After revaccination, 1/15 (6.7%) participants with prior anaphylaxis, 1/77 (1.3%) with immediate hypersensitivity not meeting criteria for anaphylaxis and 1/24 (4.2%) with other physician diagnosed hypersensitivity developed recurrent AEFI symptoms that met the BCCD for anaphylaxis. All 26 participants referred pre-vaccination, including 9 (34.6%) with history of polyethylene glycol-asparaginase reactions, were vaccinated without occurrence of immediate hypersensitivity symptoms. CONCLUSIONS: Most individuals in this national cohort who experienced a hypersensitivity event following COVID-19 vaccination and were referred for specialist review were revaccinated without AEFI recurrence, suggesting that specialist evaluation can facilitate safe revaccination.

Baked milk and egg diets revisited.

Most children with milk and egg allergy are nonreactive to modified forms of milk and egg in bakery products such as muffins because of conformational changes in proteins. These baked milk (BM) and baked egg (BE) diets have become commonplace in the management of milk and egg allergy, respectively. Current laboratory- and skin test-based diagnostic approaches remain limited in their ability to predict BM/BE tolerance, resulting in various approaches to introduce these foods. One approach to introduce BM/BE is to offer a medically supervised oral food challenge and then advise dietary introduction of baked products for children who have tolerance. Another approach is adapted from a home-based protocol of graded ingestion of BM or BE originally intended for non-IgE mediated allergy, often referred to as a "ladder." The ladder advises home ingestion of increasing amounts of BM or BE. For children who have allergy to BM or BE, the ladder is essentially oral immunotherapy, although not always labeled or recognized as such. Risk assessment and education of patients suitable for home introduction are essential. A home approach that may be called a ladder can also be used to escalate diets after demonstrated tolerance of baked forms by introducing lesser cooked forms of milk or egg after tolerating BM or BE. A randomized controlled trial provided clear evidence that baked diets can hasten the resolution of IgE-mediated milk allergy. Moreover, BM/BE foods have an emerging role in the treatment of non-IgE-mediated allergy. There is tangential evidence for BM and BE diets in the prevention of IgE-mediated allergy.

Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

When Supplemental Formula Is Essential: Overcoming Barriers to Hypoallergenic Formula Access for Patients With Food Allergies.

For food-allergic patients, hypoallergenic formulas (HFs) are medically indicated, often a primary component of the diet and essential for patient safety, health, nutrition, and overall well-being. Yet, food allergy is not included among the conditions mandated for coverage under federal health programs and private health insurance. The 2022 infant formula crisis has affected many North American families and has particularly influenced patients with food allergies who rely on a limited number of safe HF brands to safely meet their nutritional needs for growth and development. The current formula shortage further highlights the longstanding difficulties faced by families with food allergies in accessing HF. Within this context, this article focuses on chronic barriers faced by patients with food allergies in accessing HF and proposes potential solutions. Legislation is desperately needed to address HF affordability through changes in insurance reimbursement and disparities in access to HF among individuals with food allergy.

Baked Milk and Baked Egg Survey: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee.

Most milk- and egg-allergic children can tolerate milk and egg in baked forms. Some allergists have extended the use of baked milk (BM) and baked egg (BE) to advocating for the stepwise introduction of small amounts of BM and BE to children who are reactive to larger amounts of BM and BE. Little is known about the practice of introducing BM and BE and existing barriers to this approach. The purpose of this study was to gather a current assessment of the implementation of BM and BE oral food challenges and diets for milk- and egg-allergic children. We conducted an electronic survey of North American Academy of Allergy, Asthma & Immunology members offering BM and BE introduction in 2021. The response rate was 10.1% of distributed surveys (72 of 711). Surveyed allergists had a similar approach to both BM and BE introduction. Demographic features of time in practice and region of practice were significantly associated with the odds of introducing BM and BE. A wide variety of tests and clinical features guided decisions. Some allergists determined BM and BE to be appropriate for home introduction and offered this for BM and BE more often than other foods. The use of BM and BE as a food for oral immunotherapy was endorsed by almost half of respondents. Less time in practice was the most significant factor associated with offering this approach. Published recipes were used and written information was widely provided to patients by most allergists. The wide practice variabilities reveal a need for more structured guidance about oral food challenges, in-office versus home procedures, and patient education.

An update on recent developments and highlights in food allergy.

While both the incidence and general awareness of food allergies is increasing, the variety and clinical availability of therapeutics remain limited. Therefore, investigations into the potential factors contributing to the development of food allergy (FA) and the mechanisms of natural tolerance or induced desensitization are required. In addition, a detailed understanding of the pathophysiology of food allergies is needed to generate compelling, enduring, and safe treatment options. New findings regarding the contribution of barrier function, the effect of emollient interventions, mechanisms of allergen recognition, and the contributions of specific immune cell subsets through rodent models and human clinical studies provide novel insights. With the first approved treatment for peanut allergy, the clinical management of FA is evolving toward less intensive, alternative approaches involving fixed doses, lower maintenance dose targets, coadministration of biologicals, adjuvants, and tolerance-inducing formulations. The ultimate goal is to improve immunotherapy and develop precision-based medicine via risk phenotyping allowing optimal treatment for each food-allergic patient.

Nutrition and immunity: perspectives on key issues and next steps.

In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.

Precision cut intestinal slices, a novel model of acute food allergic reactions.

BACKGROUND: Food allergy affects up to 10% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS). METHODS: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0 to 24 h. Distribution of relevant cell subsets was confirmed using single nucleus RNA sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker, and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed. RESULTS: PCIS viability was maintained for 24 h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction. CONCLUSION: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.

BACKGROUND: Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution, and treatment choice. OBJECTIVE: We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity. METHODS: We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX. RESULTS: Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and TH2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNF-α, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg-cell and Teff compartments, studied by Mass Cytometry by Time-Of-Flight, were skewed toward the TH2 compartment, especially in typical IPEX. CONCLUSIONS: Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity.

Platelet Activating Factor (PAF): A Mediator of Inflammation.

Platelet-activating factor (PAF) is a phospholipid-derived mediator with an established role in multiple inflammatory states. PAF is synthesized and secreted by multiple cell types and is then rapidly hydrolyzed and degraded to an inactive metabolite, lyso-PAF, by the enzyme PAF acetylhydrolase. In addition to its role in platelet aggregation and activation, PAF contributes to allergic and nonallergic inflammatory diseases such as anaphylaxis, sepsis, cardiovascular disease, neurological disease, and malignancy as demonstrated in multiple animal models and, increasingly, in human disease states. Recent research has demonstrated the importance of the PAF pathway in multiple conditions including the prediction of severe pediatric anaphylaxis, effects on blood-brain barrier permeability, effects on reproduction, ocular diseases, and further understanding of its role in cardiovascular risk. Investigation of PAF as both a biomarker and a therapeutic target continues because of the need for directed management of inflammation. Collectively, studies have shown that therapies focused on the PAF pathway have the potential to provide targeted and effective treatments for multiple inflammatory conditions.

Platelet-activating factor acetylhydrolase is a biomarker of severe anaphylaxis in children.

BACKGROUND: There is limited ability to predict the severity of allergic reactions in children. Data derived predominantly from adults have implicated the platelet-activating factor pathway as a potential contributor to severe anaphylaxis. In this study, we sought to prospectively assess involvement of key components of the platelet-activating factor pathway in pediatric patients with anaphylaxis. METHODS: Forty-six pediatric patients (<18 years) presenting with acute anaphylaxis were assessed. Anaphylaxis severity was graded and serum anaphylaxis markers were measured acutely and in 36 children who returned for follow-up >4 weeks after their acute presentation. These markers were compared with pediatric laboratory reference sera. RESULTS: Severe anaphylaxis was experienced by 12/46 (26%) and mild-moderate anaphylaxis in 34/46 (74%) children. Platelet-activating factor acetylhydrolase (PAF-AH) activity was inversely associated with severe anaphylaxis: 9/12 children with severe anaphylaxis had reduced PAF-AH activity as compared with 14/34 with mild-moderate anaphylaxis (p < .05). Furthermore, 3/3 children who required intensive care had markedly reduced mean PAF-AH (nmol/ml/min) (13.73, 95%CI: 7.42-20.03) versus 20/23 who required ward/emergency department care (17.81, 95%CI: 16.80-18.83; p < .05). In children with anaphylaxis, PAF-AH during acute anaphylaxis was unchanged relative to the child's basal levels (mean, 17.26, 95%CI: 16.10-18.42 vs 17.50, 95%CI: 16.21-18.78, p = .63) and was lower than healthy pediatric controls (mean 19.21; 95%CI:18.21-20.21; p < .05). CONCLUSION: Decreased serum PAF-AH activity is a biomarker of severe anaphylaxis. Levels of this enzyme do not change from basal levels during acute anaphylaxis. Our results show that PAF-AH is a biomarker of anaphylaxis severity in children. This key regulatory enzyme may modulate susceptibility to severe anaphylaxis.

Elevated Cow's Milk-Specific IgE Levels Prior to Oral Immunotherapy Decrease the Likelihood of Reaching the Maintenance Dose.

BACKGROUND: Food desensitization via oral immunotherapy (OIT) is gaining acceptance in clinical practice. Owing to adverse reactions, the duration of the buildup phase until a maintenance dose is achieved may be prolonged, and in a minority of cases, OIT is stopped. OBJECTIVE: We aimed to assess factors associated with the probability of reaching the maintenance dose in cow's milk (CM) OIT. METHODS: We collected data from patients undergoing CM OIT at the Montreal Children's Hospital, BC Children's Hospital, and Hospital for Sick Children. We compared univariable and multivariable Cox regressions to evaluate sociodemographic factors, comorbidities, clinical characteristics, and biomarkers at study entry associated with the likelihood of reaching a maintenance dose of 200 mL of CM. RESULTS: Among 69 children who reached 4 mL of milk, the median age was 12 years (interquartile range, 9-15 years); 59% were male. Median duration of buildup phase from 4 to 200 mL was 24.0 weeks (interquartile range, 17.7-33.4 weeks). After adjusting for age and sex, higher baseline levels of specific IgE antibodies for α-lactalbumin (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.67-0.95), ß-lactoglobulin (HR = 0.86; 95% CI, 0.76-0.98), casein (HR = 0.82; 95% CI, 0.72-0.94), and total CM (HR = 0.79; 95% CI, 0.65-0.97) were associated with a decreased probability of reaching maintenance. In addition, for every 10-mL increase in CM tolerated at entry challenge, the probability of reaching maintenance increased by 10%. CONCLUSIONS: The data suggest that higher levels of CM-specific IgE decreased the likelihood of reaching maintenance, whereas an increased cumulative CM dose at entry challenge increased the likelihood. Assessing these factors before therapy may assist in predicting the success of CM OIT.

Moderate-to-severe lower respiratory tract infection in early life is associated with increased risk of polysensitization and atopic dermatitis: Findings from the CHILD Study.

Background: Respiratory infections in infancy are associated with the development of allergic asthma and atopy. Delineating whether symptomatic infections are a marker of atopic predisposition or contribute to atopic development is important for preventive strategies. We hypothesized that early, severe lower respiratory tract infections (LRTIs) may be a risk factor for the development of atopic disease. Objective: Our aim was to determine whether clinically defined, moderate-to-severe LRTIs in infancy are associated with the development of atopic dermatitis and allergic sensitization at preschool age. Methods: LRTI timing and severity in the first 18 months of life was defined by using the Canadian Healthy Infant Longitudinal Development study questionnaires. Polysensitization and atopic dermatitis were determined by standardized skin prick testing and structured clinical assessments. Longitudinal associations between LRTI severity and clinical outcomes at ages 3 years and 5 years were determined by adjusted repeated measures generalized estimation equations. Results: Moderate-to-severe LRTIs were associated with increased odds of polysensitization (odds ratio = 1.91 [95% CI = 1.16-3.15]; P = .014) and atopic dermatitis (odds ratio = 2.19 [95% CI 1.41-3.39]; P < .001) as compared with the odds in children with no history of LRTI in the first 18 months of life. The association between moderate-to-severe LRTI and polysensitization or atopic dermatitis remained robust after adjusting for sex; study site; breast-feeding duration; and mother, father, or both-parent atopy or asthma. Conclusions: These results highlight severe infant LRTI as an important risk factor for allergic and atopic disease (ie, polysensitization and atopic dermatitis), and they suggest that this risk is independent of maternal in utero environment, both-parent history of asthma, and both-parent genetic predisposition.

Efficacy, effectiveness and other patient-centered outcomes of oral immunotherapy.

Oral immunotherapy (OIT) is the medically supervised ingestion of a food allergen. Understanding of the expected outcomes of OIT allow for risk-benefit assessments for patient-centered decisions. The efficacy of OIT to achieve desensitization in children has been confirmed in multiple meta-analyses, even with vastly disparate study populations and methodologies. Most children initiated on OIT will achieve the ability to eat more allergen before experiencing an allergic reaction than if they continue to avoid their allergen. This effect is diminished without regular ingestion. Previous meta-analyses showed increased allergic reactions on OIT versus avoidance or placebo due to the dosing itself; however, a recent meta-analysis showed that peanut OIT in children did not lead to an increase in allergic reactions. Analysis of emerging data suggests that OIT may reduce reactions to accidental exposures over time. Important patient-centered outcomes, including reaction avoidance or amelioration, and psychosocial impacts and/or quality of life, and studies of more demographically representative populations are also necessary.